Promotion of Knee Cartilage Degradation by IκB Kinase ε in the Pathogenesis of Osteoarthritis in Human and Murine Models
Promotion of Knee Cartilage Degradation by IκB Kinase ε in the Pathogenesis of Osteoarthritis in Human and Murine Models
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IκB 激酶 ε 在人类和小鼠模型骨关节炎发病机制中促进膝关节软骨降解
DOI：
10.1002/art.42421
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发表时间：
2023
影响因子：
13.3
通讯作者：
Nakashima Yasuharu
中科院分区：
文献类型：
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作者：
Uchida Taisuke;Akasaki Yukio;Sueishi Takuya;Kurakazu Ichiro;Toya Masakazu;Kuwahara Masanari;Hirose Ryota;Hyodo Yuki;Tsushima Hidetoshi;Lotz Martin K.;Nakashima Yasuharu
目的NF - κB信号通路是骨关节炎（OA）的重要调节因子，而i - κB激酶ε (IKKε)调控NF - κB通路。本研究旨在确定IKKε在OA发病机制中的功能参与以及IKKε抑制作为一种调节治疗的有效性。方法用免疫组织化学方法分析正常和OA人膝关节中sikkε的表达。使用人软骨细胞进行功能增益或功能丧失实验。此外，手术诱导小鼠骨性关节炎，然后每5天向左膝关节内注射BAY - 985（一种IKKε/TANK结合激酶1抑制剂），持续8周。随后检查小鼠软骨损伤和炎症的组织学特征。结果人OA软骨组织中kkε蛋白表达升高。在体外，在人OA软骨细胞中使用小干扰RNA敲除IKKε或使用BAY - 985治疗后，OA相关因子的表达水平下调。相反，IKKε过表达显著增加OA相关分解代谢介质的表达。Western blot结果显示，IKKε过表达增加了IκBα和p65的磷酸化。在体内，在小鼠膝关节关节内注射BAY - 985可通过NF - κB信号通路减轻OA相关软骨退化和痛觉过敏。这些结果表明IKKε通过NF - κB信号介导的分解代谢反应调节软骨降解，这可能是OA治疗的潜在靶点。此外，BAY‐985可能作为OA药物中主要的疾病修饰化合物。
ObjectiveNF‐κB signaling is an important modulator in osteoarthritis (OA), and IκB kinase ε (IKKε) regulates the NF‐κB pathway. This study was undertaken to identify the functional involvement of IKKε in the pathogenesis of OA and the effectiveness of IKKε inhibition as a modulatory treatment.MethodsIKKε expression in normal and OA human knee joints was analyzed immunohistochemically. Gain‐ or loss‐of‐function experiments were performed using human chondrocytes. Furthermore, OA was surgically induced in mice, followed by intraarticular injection of BAY‐985, an IKKε/TANK‐binding kinase 1 inhibitor, into the left knee joint every 5 days for 8 weeks. Mice were subsequently examined for histologic features of cartilage damage and inflammation.ResultsIKKε protein expression was increased in human OA cartilage. In vitro, expression levels of OA‐related factors were down‐regulated following knockdown of IKKε with the use of small interfering RNA in human OA chondrocytes or following treatment with BAY‐985. Conversely, IKKε overexpression significantly increased the expression of OA‐related catabolic mediators. In Western blot analysis of human chondrocytes, IKKε overexpression increased the phosphorylation of IκBα and p65. In vivo, intraarticular injection of BAY‐985 into the knee joints of mice attenuated OA‐related cartilage degradation and hyperalgesia via NF‐κB signaling.ConclusionThese results suggest that IKKε regulates cartilage degradation through a catabolic response mediated by NF‐κB signaling, and this could represent a potential target for OA treatment. Furthermore, BAY‐985 may serve as a major disease‐modifying compound among the drugs developed for OA.
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影响因子：
3.3
作者：
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通讯作者：
G. Wu
影响因子：
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作者：
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通讯作者：
Mes-Masson AM
影响因子：
7
作者：
Kurakazu I;Akasaki Y;Tsushima H;Sueishi T;Toya M;Kuwahara M;Uchida T;Lotz MK;Nakashima Y
通讯作者：
Nakashima Y
NEMO/IKK g 缺陷小鼠的严重肝变性和缺乏 NF - k B 激活
DOI：
--
发表时间：
2000
期刊：
影响因子：
--
作者：
D. Rudolph;W. Yeh;A. Wakeham;B. Rudolph;D. Nallainathan;J. Potter;A. Elia;T. Mak
通讯作者：
T. Mak
影响因子：
--
作者：
Little, C. B.;Barai, A.;Burkhardt, D.;Smith, S. M.;Fosang, A. J.;Werb, Z.;Shah, M.;Thompson, E. W.
通讯作者：
Thompson, E. W.